Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression.

Ferroptosis is a regulated necrosis driven by iron-dependent lipid peroxidation. Mitochondria play vital roles in ferroptosis. Mitochondrial dynamics is critical for the health of mitochondria and cells. But how this process regulates ferroptosis is not fully understood. Here, we found that mitochondrial fission is induced during ferroptosis. Disruption of mitochondrial dynamics by impeding the expression of the central players of mitochondrial dynamics control, dynamin-related protein 1 (DRP1) and Mitofusion1/2, or modifying the expression of optic atrophy 1 (OPA1) inhibits ferroptosis. Mechanistically, a defect in mitochondrial dynamics homeostasis increases the ratio of [AMP+ADP]/[ATP], thus activating AMP-activated protein kinase (AMPK), which further phosphorylates nuclear factor erythroid 2-related factor 2 (NRF2) and promotes NRF2 nuclear translocation. Subsequently, NRF2 triggers ferroptosis suppressor 1 (FSP1) upregulation, which renders the cells resistant to ferroptosis. Importantly, mitochondrial fusion promoter M1 can mitigate the chemotoxicity induced by doxorubicin without compromising its anti-cancer efficacy. Collectively, the results of this study demonstrate the crucial role of mitochondrial dynamics in ferroptosis and indicate a potential therapeutic protective approach for chemotoxicity.